We have made substantial progress towards Aims 1-4. Specifically: a) We have determined that 3 nm iron oxide nanoparticles can be reliably fabricated, in collaboration with the NIH image probes development core. These serve as good T1 MRI contrast agents. b) We have developed several camelid VHH antibody fragment targeting domains for pathological targets relevant to neurological disease, and made specific modifications to enhance the affinity of the targeting domains. Several additional targeting domains are under development. c) We have validated the binding specificity of a blood-brain barrier transcytosis functionalization domain. We are creating additional blood-brain barrier transcytosis domains and testing them for optimal transcytosis. d) We have determined appropriate methods to prevent fouling of nanoparticles in human plasma using PEG coatings, and are working on assessing peptide-based coatings as well. e) We have successfully assembled nanoparticles using these 4 components, and demonstrated that they retain their properties after assembly. f) We have determined that MP2RAGE MRI sequences have excellent properties for detecting T1 MRI contrast agents in both mice (at 4.7T and 9.4T) and humans (at 3T). Specifically, the test-retest reliability for MP2RAGE MRI was found to be superior to other T1 methods given similar scan times. g) We have performed initial in vivo experiments in mice, and have developed initial methods for assessing molecular contrast agent kinetics using infrared tracking.